Spontaneous Generation of Prion Infectivity in Fatal Familial Insomnia Knockin Mice

A crucial tenet of the prion hypothesis is that misfolding of the prion protein (PrP) induced by mutations associated with familial prion disease is, in an otherwise normal mammalian brain, sufficient to generate the infectious agent. Yet this has never been demonstrated. We engineered knockin mice...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2009-08, Vol.63 (4), p.438-450
Main Authors: Jackson, Walker S., Borkowski, Andrew W., Faas, Henryk, Steele, Andrew D., King, Oliver D., Watson, Nicki, Jasanoff, Alan, Lindquist, Susan
Format: Article
Language:English
Subjects:
Amino Acid Substitution - genetics
Animals
Behavior
Creutzfeldt-Jakob disease
Experiments
Gene Knock-In Techniques - methods
Humans
HUMDISEASE
Hypotheses
Infections
Insomnia
Insomnia, Fatal Familial - diagnosis
Insomnia, Fatal Familial - genetics
Insomnia, Fatal Familial - physiopathology
Mice
Mice, Transgenic
MOLNEURO
Mutation
Neuropathology
NMR
Nuclear magnetic resonance
Pathology
Prions
Prions - administration & dosage
Prions - biosynthesis
Prions - genetics
PROTEINS
Spongiform encephalopathies
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Summary:A crucial tenet of the prion hypothesis is that misfolding of the prion protein (PrP) induced by mutations associated with familial prion disease is, in an otherwise normal mammalian brain, sufficient to generate the infectious agent. Yet this has never been demonstrated. We engineered knockin mice to express a PrP mutation associated with a distinct human prion disease, fatal familial insomnia (FFI). An additional substitution created a strong transmission barrier against pre-existing prions. The mice spontaneously developed a disease distinct from that of other mouse prion models and highly reminiscent of FFI. Unique pathology was transmitted from FFI mice to mice expressing wild-type PrP sharing the same transmission barrier. FFI mice were highly resistant to infection by pre-existing prions, confirming infectivity did not arise from contaminating agents. Thus, a single amino acid change in PrP is sufficient to induce a distinct neurodegenerative disease and the spontaneous generation of prion infectivity.
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2009.07.026